tbuckley/cabot-search huggingface dataset:
DDEL-07. BARRIER TO PROGRESS: DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) INDUCES A TIGHTENED BLOOD-BRAIN BARRIER PHENOTYPE
Authors: Caitlin Ung, Dannielle Upton, Pooja Venkat, Ruby Pandher, Chelsea Mayoh, Maria Tsoli, David Ziegler
Journal: Neuro-Oncology (2023)

Abstract DIPG is an incurable paediatric brainstem tumour. Treatments have been significantly hindered by the necessity for drugs to penetrate the blood-brain barrier (BBB). We, and others, have shown that the BBB remains intact in DIPG, and it is thought that the BBB in the brainstem may be even less permeable in the presence of DIPG tumor cells. We performed in vivo studies in orthotopic DIPG mouse models that showed higher efficacy of mTOR inhibitor, temsirolimus, in cortex-injected DIPG compared to brainstem-injected DIPG. Analysis showed significantly increased survival, higher temsirolimus levels and decreased proliferating tumour cells in the cortex. Subsequently, the effect of DIPG on brain vasculature was interrogated by single-cell RNA sequencing. Microvascular endothelial cells were isolated from the brainstem and cortex, where DIPG cells or Matrigel were implanted. Transcriptomic analysis of DIPG-injected brainstem uncovered significant downregulation of inflammatory pathways, especially P38MAPK, downregulation of antigen presentation, and increased transporter Mfsd2a, suggesting a tightened BBB. Apoptotic signalling pathways were significantly upregulated, particularly MCL-1. Further analysis into cortex-injected DIPG revealed downregulation of interferon β pathways, suggesting a leakier phenotype. To overcome the tightened barrier in the brainstem, MCL-1 inhibitor S63845, was investigated as a BBB modulator. S63845 significantly reduced transendothelial electrical resistance, increased tracer dye leakage in an in vitro BBB transwell model with DIPG and decreased protein expression of claudin-5. In vivo, S63845 increased permeability to 3kDa Texas-red dextran after a single dose in DIPG mouse models. Overall, this study revealed that DIPG directly affects endothelial cell pathways associated with BBB permeability, resulting in a tightened BBB and reduced therapeutic efficacy. S63845 represents a promising BBB modulator that can be easily administered and may facilitate the delivery of therapeutics through the constricted BBB. This discovery has the potential to enhance the activity of anti-DIPG therapeutics that were previously considered impenetrable.
CTNI-67. FIRST IN HUMAN STUDY OF DSP-0390, AN ORAL EMOPAMIL BINDING PROTEIN (EBP) INHIBITOR, IN RECURRENT HIGH-GRADE GLIOMA (HGG): PRELIMINARY RESULTS
Authors: Yoshiki Arakawa, Samuel Goldlust, Howard Colman, David Reardon, Mary Welch, Shigeru Yamaguchi, Nicholas Butowski, Jian Li, Shuichi Iino, Gregory Song, Aimee Jackman, Yuran Xie, Marie-Claire Wagle, Claudia Lebedinsky, Yoshitaka Narita
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Cholesterol in the brain is derived wholly from de novo biosynthesis as the blood-brain barrier prevents uptake from the circulation. The overexpression of cholesterol synthesis genes is associated with decreased survival in glioblastoma (GBM), suggesting that gliomas may be sensitive to the inhibition of cholesterol biosynthesis. DSP-0390 is an investigational small molecule that inhibits EBP, a key enzyme in cholesterol biosynthesis. Preclinical studies demonstrated antitumor activity of DSP-0390 in orthotopic xenograft GBM models. METHODS This phase I dose escalation study aims to assess the safety, PK, PD, and preliminary antitumor activity of oral DSP-0390 monotherapy for recurrent HGG (NCT05023551). Key eligibility criteria include histologically confirmed grade III or IV glioma (WHO 2016); treatment with ≥ 1 prior therapy; no treatment options beyond standard of care; KPS ≥ 70. RESULTS As of 9 May 2023, 24 patients (37.5% women) were enrolled across 6 dose levels (20 mg QD to 240 mg QD) with a median age of 51 years (range 24-76) including 17 (70.8 %) with GBM, 3 (12.5%) with anaplastic astrocytoma and 2 (8.3%) with anaplastic oligodendroglioma. Ten patients (41.7%) had IDH mutant tumors. Four patients (16.7%) were on stable dose of corticosteroids at baseline, of which 2 were able to discontinue or dose reduce the corticosteroid while on DSP-0390. There were no reported DLTs. The most common treatment-related TEAEs included grade 1 or 2 nausea (7 patients [29.2%]) and alanine aminotransferase increased (6 patients [25.0%]). Only one grade 3 related AE (dry skin) was noted. Two patients with IDH mutant grade 3 glioma had tumor reduction and remain on DSP-0390 for ≥ 9 months. Dose dependent changes in PK and PD were observed. CONCLUSIONS DSP-0390 has been well tolerated to date with dose escalation ongoing. A dose response relationship was observed between PK and PD biomarkers.
NIMG-52. CORRELATION OF BIDIMENSIONAL AND VOLUMETRIC TUMOR SIZING IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA
Authors: John Kim, Thomas Nelson, Gilbert Youssef, Rifaquat Rahman, Omar Arnaout, Wenya Linda Bi, Daniel Cagney, Yuh-Shin Chang, Matthew DeSalvo, Thomas Flood, Elizabeth Gerstner, Luis Nicolas Gonzalez Castro, Jeffrey Guenette, Albert Kim, Eudocia Lee, Jose Ricardo McFaline-Figueroa, Christopher Potter, David Reardon, Patrick Wen, Raymond Y Huang
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is the most common malignant primary nervous system tumor and remains incurable with a poor prognosis despite current therapy. The standard for monitoring response to treatment, as defined by the Response Assessment in Neuro-Oncology (RANO) criteria, relies on a bidimensional (2D) measurement product of T1-gadolinium enhancing disease. However, due to the variability of bidimensional tumor characterization, there is considerable interest in volumetric segmentation to assess tumor burden, which could be implemented using machine learning models offering workflow automatization. METHODS In this study, we evaluate a commercially available automated tumor segmentation tool and correlate its volumetric output to the manual assessment of bidimensional 2D enhancing tumor burden by experts. MRI examinations during systemic treatment for two retrospective cohorts of patients with either newly diagnosed (nGBM) or recurrent GBM (rGBM) were assessed. The 2D diameter product in cm^2 of enhancing tumor was determined by blinded readers and volumetric segmentations in cm^3 were automatically generated. Spearman's correlation between the manual 2D and automated volume measurements was calculated for each cohort. RESULTS 315 patients with nGBM, and 482 with rGBM were evaluated, comprising 3073 total brain MRIs in the nGBM cohort and 2439 MRIs in the rGBM cohort. Spearman's correlation between the manual 2D and automated volumetric measurements was 0.7463 (0.730, 0.762) in the nGBM cohort and 0.8598 (0.849, 0.870) in the rGBM cohort. CONCLUSION Automated segmentation tools have the potential to revolutionize radiology workflows and increase sensitivity to subtle changes on imaging. However, the differential performance of this volumetric assessment confirms the need for further refinement and customization of such automated tools to account for tumor- and patient-specific factors.
QLTI-13. RETROSPECTIVE REVIEW OF THE DIAGNOSTIC YIELD OF CEREBROSPINAL FLUID (CSF) ANALYSIS IN DIAGNOSIS OF CENTRAL NERVOUS SYSTEM (CNS) LYMPHOMA IN A COMMUNITY NEURO ONCOLOGY CENTER
Authors: Christine Lu-Emerson, Donna Lawlor, Cushing Deborah, Anand Rughani, Robert Christman, Jeffrey Florman
Journal: Neuro-Oncology (2023)

Abstract Central nervous system (CNS) lymphoma can be a challenging disease to diagnose. Both primary and secondary CNS lymphoma often result in poor outcomes rendering early diagnosis and treatment essential. Traditionally, diagnostic modalities include surgery, cerebral spinal fluid (CSF) cytologic analysis, vitrectomy, and chorioretinal biopsy. Radiographic and clinical presentation can widely vary between patients, further enhancing diagnostic dilemma. We present a retrospective study from a community neuro oncology center analyzing the utility of CSF analysis in the diagnosis of CNS lymphoma. Between 2018-2022, 26 CNS lymphoma patients were identified of which 22 (85%) were primary CNS lymphoma patients. Median age of diagnosis was 68.5 years, and 21 (81%) of the patients were immunocompetent. 13 (50%) of the patients underwent CSF analysis, including cytology and flow cytometry), prior to biopsy and none (0%) yielded a positive diagnosis of CNS lymphoma. While mean CSF volume for cytology was slightly more than 3 cc of fluid, patients who had 5-10 cc of fluid sent for cytology also yielded a negative result for CNS lymphoma. For all patients, median duration from presentation of symptoms to surgery was 10.5 days. However, when divided between patients who proceeded straight to biopsy (CSFsecond) versus those who underwent CSF analysis prior to biopsy (CSFfirst), the duration from presentation of symptoms to surgery was 6 days versus 11 days, respectively. 10 patients in the CSFfirst group were not on steroids at the time of lumbar puncture whereas only 4 patients in the CSFsecond group were not on steroids at time of biopsy suggesting that steroid use did not seem to influence the yield of either diagnostic modalities. Our experience suggests that CSF analysis in community settings should be reserved only for staging and that surgical biopsy should be pursued as soon as the diagnosis of CNS lymphoma is considered.
EPID-17. ANTIBODY REACTIVITY TO VARICELLA ZOSTER VIRUS IS ASSOCIATED WITH IMPROVED GLIOMA SURVIVAL AND IS MODIFIED BY GERMLINE HLA POLYMORPHISMS
Authors: Stephen Francis, Geno Guerra, Helen Hansen, John Wiencke, Margaret Wrensch
Journal: Neuro-Oncology (2023)

Abstract Antigenic reactivity towards varicella zoster virus (VZV) has shown a consistent reduction in glioma risk across multiple studies on multiple continents. To our knowledge this is the virus to be robustly associated with reduced risk of any cancer. Our recent work has shown that high VZV reactivity is also assumed with improved glioma prognosis. Using the UKBioBank we have previously shown that germline HLA polymorphism, rs9273325, significantly effects reactivity to VZV. In this study we investigate the VZV glioma survival association in the context of germline HLA polymorphisms. METHODS: We measured quantitative IgG reactivity towards VZV gE, and conducted genome wide array based genotyping in 891 adults with glioma. Associations of patient IgG levels (1st quartile vs. quartiles 2,3,4) with overall survival were estimated using Cox models adjusted for age, sex, self-reported race, surgery type, dexamethasone usage at blood draw. RESULTS: VZV seroreactivity was significantly associated with reduced mortality (HR=0.83, 95% CI: 0.70-0.99; p=0.034), as expected from our previous study. Among patients with rs9273325-GG, higher levels of VZV antibodies were associated better prognosis (HR=0.75, 0.62-0.92; p=0.005), but in the rs9273325-GA/AA strata this relationship with VZV antibodies was not observed (HR=0.94, 0.66-1.35; p=0.75). Similar results were observed in grade IV gliomas, IDHwt GBMs. CONCLUSIONS: Strong antibody response to VZV is associated with improved glioma prognosis and the effect of VZV reactivity on glioma survival is modified by a specific HLA polymorphism, a Gene x Virus interaction, that is unlikely due to chance. This study highlights the importance of accounting for HLA variation in immune related studies, including oncolytic viral therapies. Our findings also point towards a potentially MHC mediated mechanism by which VZV could be priming an immune response targeting glioma cells. Further investigations into this mechanism and VZV/shingles vaccination as a potential glioma therapeutic are warranted.
PATH-38. MOLECULAR CHARACTERIZATION OF GLIOMA TISSUE AFTER TTFIELDS TREATMENT
Authors: Christian Mawrin, Michael Luchtmann, Elmar Kirches
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION This study aims to investigate the molecular characterization of glioma tissue after treatment with Tumor Treating Fields (TTFields). TTFields therapy utilizes low-intensity alternating electric fields to disrupt cancer cell division and is approved for treatment of glioblastoma as well as mesothelioma. Understanding the histological, cellular, and epigenetic changes induced by TTFields treatment can help identify biomarkers for TTFields response and elucidate potential resistance mechanisms. MATERIAL AND METHODS Tumor tissue samples (FFPE) were collected from newly diagnosed glioblastoma patients treated with TTFields, including both the primary tumor and matching recurrent tumor samples. Molecular analyses using a glioma-targeted next-generation sequencing (NGS) panel sequencing were performed to assess genetic alterations in both primary and recurrent tumors. RESULTS Genomic analysis of paired samples from 5 patients (4 glioblastoma, one astrocytoma, IDH-mutated WHO grade 4) revealed an identical molecular pattern (TERT mutation) in 2 patients, one patient with a gain of an ATRX mutation in the recurrent tumor, one patient with gain of two EGFR mutations, and the IDH1-mutated astrocytoma showing a loss of a TP53 mutation in the recurrent tumor. CONCLUSION This pilot study provides valuable insights into the molecular characterization of glioma tissue after TTFields treatment. It appears that the spectrum of mutations may vary in a substantial number of TTF-treated tumors. Further validation and larger-scale studies are needed to confirm and expand upon these preliminary results.
DISP-07. GLIOMAS IN HIV-POSITIVE PATIENTS CAN BE IDH-MUTANT OR -WILDTYPE
Authors: David Ormond, Douglas Ney, B K DeMasters
Journal: Neuro-Oncology (2023)

Abstract Recent review has emphasized that glioblastoma (GBM) in persons living with human immunodeficiency virus (HIV)(PLWH) is “severely underreported in the literature” (PMID 35857248), since only 24 cases could be identified. This 2022 study concluded that overall survival in this patient group is less than in persons who are HIV-negative. Given the predominantly single-case reports in the literature, it is not surprising that “data remains limited”. To this end, we report our 15-year experience with patients with HIV-positivity diagnosed at our institution. Text word search of Department of Pathology databases, 2008-2023, with review of histological sections and the medical record. 7 patients living with PLWH were identified, all males, ages at diagnosis 44-61 years, median 58 years. 3 had tumors that met histological criteria for GBM, IDH-wildtype, WHO grade 4, 1 had GBM by modern molecular criteria and 2 had astrocytoma, IDH-mutant, WHO grade 4. One of the latter had co-existent diffuse high grade B cell lymphoma intimately admixed within his glioma while the final patient had multifocal brain lesions of different neuroimaging appearances, with the bifrontal tumor consistent with GBM and posterior frontal lesions suspicious for progressive multifocal leukoencephalopathy. At the time of tumor diagnosis, 1 had HIV for 20+ years, a second was well controlled with normal CD4 count and a third had not yet been on anti-retroviral agents. Survival was poor, with 2 PLWH with IDH-mutant tumors succumbing at 2 and 4 months and 3 with GBMs at 7, 12 and 32 months; a 4th is alive at 6 months. PLWH can develop various glial tumor types including both IDH-mutant and IDH-wildtype tumors, strongly suggesting co-incident rather than causal relationship. Tumors may be first diagnosed at varying stages of their immunodeficiency disorder; survival is poor even for PLWH with IDH-mutant grade 4 tumor.
CNSC-34. BAF60C/SMARCD3 MODULATES CEREBELLUM DEVELOPMENT AND MEDULLOBLASTOMA METASTASIS
Authors: Han Zou, Yash Patel,, Chaim Sneiderman, Anjali Talluru, Allen Zheng, Thomas Pearce, Sameer Agnihotri, Gary Kohanbash, Ian Pollack, Baoli Hu
Journal: Neuro-Oncology (2023)

Abstract Medulloblastoma (MB), the most common type of embryonal tumor in children, is a fast-growing and heterogeneous brain tumor arising in the cerebellum. The molecular characterization of MB reveals four major subgroups (WNT, SHH, Group 3, and Group 4) and Group 3 is the most aggressive and malignant, characterized by frequent metastasis at diagnosis and the worst prognosis. We have recently found that BAF60C/SMARCD3 is highly expressed in Group 3 MB and associated with poor prognosis. Mechanistically, BAF60C/SMARCD3 hijacks a neurodevelopmental epigenetic program mediated by Disabled1 (DAB1)-Reelin signaling to promote metastatic dissemination in MB. Using single-cell RNA sequencing data of developing mouse and human cerebellum, we found that BAF60C/SMARCD3 expression in Purkinje cells (PCs) is upregulated during embryonic and early postnatal stages, but downregulated during the late postnatal stage of cerebellar development. To examine the effect of BAF60C/SMARCD3 depletion on PC migration and positioning during embryonic and postnatal stages of cerebellar development, we generated targeted knockout mice by crossing the PC-specific Cre mouse (L7Cre-2 and FoxP2-Cre) with the Smarcd3flox/flox mouse. We found that BAF60C/SMARCD3 depletion significantly influences embryo development in FoxP2-Cre; Smarcd3flox/flox but not in L7Cre-2; Smarcd3flox/flox mice, further supporting the expression of BAF60C/SMARCD3 in early stage (Foxp2 +) but not in the late stage (L7/Pcp2+) during cerebellum development. To determine whether BAF60C/SMARCD3 contributes to MB development, we injected lentivirus-carrying constitutively active MYCS62D with/without BAF60C/SMARCD3 in C57BL/6J mice. Interestingly, we found that MYCS62D with BAF60C/SMARCD3 can induce a spontaneous Group3-like MB with strong metastatic dissemination compared to MYCS62D without BAF60C/SMARCD3. These results demonstrate that BAF60C/SMARCD3 plays a pivotal role in PC biology and cerebellar development, and tumor cells hijack BAF60C/SMARCD3-Reelin signaling to promote tumor metastasis in MB.
EPID-01. ANTINEOPLASTIC, RADIATION, AND SYNCHRONICITY EFFECTS ON BRAIN METASTASIS SURVIVAL: A RETROSPECTIVE POPULATION-BASED STUDY
Authors: Jordina Rincon-Torroella, Kelly Jiang, Megan Parker, Joshua Materi, Tej Azad, David Kamson, Lawrence Kleinberg, Xiaobu Ye, Chetan Bettegowda
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Brain metastases (BM) are the most common central nervous system tumors. The impact of oncological treatment on the prevention of BM is not well-defined. We report the effects of chemotherapy and radiotherapy directed at primary cancer on synchronous and metachronous BM survival. METHODS A large nationwide multi-institutional claims-based platform (TriNetX Diamond Network) was queried. Patients diagnosed during 2013-2023 with the 15 most common primary cancers that metastasize to the brain were included. Metachronous was defined as BM diagnosed &amp;gt; 2 months after primary cancer. Cohorts were propensity score matched for age, extracranial metastasis, and adjuvant therapy. Kaplan-Meier plots were used to compare survival. RESULTS 113,827 (38%) patients with synchronous and 187,036 (62%) with metachronous BM were identified. Patients with synchronous BM had 26 months shorter median survival compared to metachronous BM (11 vs. 37 months, HR 2.17, 95%CI 2.14-2.19, P&amp;lt; 0.0001). However, no survival advantage was observed from the time of BM diagnosis (11 vs. 12 months, HR 1.06, 95%CI 1.05-1.08, P=0.411). Antineoplastic treatment prior to BM improved median BM-free survival by 13 months (4 vs. 18 months, HR 1.66, 95%CI 1.77-1.82, P &amp;lt; 0.0001) and median OS by 17 months (25.15 vs. 42.26 months, HR 1.48, 95%CI 1.46-1.51, P&amp;lt; 0.0001). Radiation therapy prior to BM incurred a significant but smaller increase in median BM-free survival by 6 months (5 vs. 11 months, HR 1.27, 95%CI 1.26-1.29, P&amp;lt; 0.0001) and median OS by about 3 months (30.13 vs. 32.82 months, HR 1.06, 95%CI 1.04-1.08, P &amp;lt; 0.0001). CONCLUSION Once BM is diagnosed, the synchronicity of diagnosis does not predict survival. Antineoplastic and radiation treatment directed at primary cancer may improve BM-free survival and OS. Studies characterizing the BM-free effects of molecular markers, chemotherapy, and radiotherapy are necessary to improve screening, prevention, and treatment.
IMMU-53. MONITOR THE IMMUNE MICROENVIRONMENT AND SYSTEMIC IMMUNE EFFECTS IN PEDIATRIC BRAIN TUMORS – THE MIMIC PROGRAM
Authors: Raoull Hoogendijk, Tiago Carvalheiro, Julie Lammers, Mariëtte Kranendonk, Joyce Meesters-Ensing, Hendrik Stunnenberg, Marcel Kool, Jens Bunt, Anneke Heutinck, Lisette Adams, Kirsten Van Baarsen, Stefan Nierkens, Friso Calkoen, Jasper van der Lugt
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Dismal outcomes of pediatric high-grade CNS tumors demand new therapeutic strategies. A better understanding of the immune system may contribute to designing better immunotherapies for these children. The MIMIC program (Dutch Trial Registry NL8967) is a prospective observational longitudinal cohort study, conducted in patients with newly diagnosed or relapsed high-grade CNS tumors with the aim of characterizing and quantifying changes in immune parameters at diagnosis and during treatment. METHODS All patients with a newly diagnosed or relapsed high-grade CNS tumor are included after obtaining informed consent. Patient study material is collected longitudinally and includes tumor tissue (TT), Cavitron Ultra Sonic Aspirator (CUSA) material and optional bone marrow aspiration (BM) at diagnosis and relapse. Cerebrospinal fluid (CSF), peripheral blood (PB) and fecal samples (FS) at diagnosis, 3 months, 6 months, 12 months, relapse and additionally collection of CSF and FS at 14 days. Furthermore, FS is collected from patient siblings as a reference. RESULTS The MIMIC program has opened in June 2021 in the Princess Máxima Center, the national pediatric oncology center in the Netherlands, including so far 47 patients (out of ~60 eligible patients annually). More than 400 samples, out of which 46 TT, 34 CUSA, 65 CSF, 14 BM, 143 PB, and 105 FS have been collected. All samples are subject to extensive immunological profiling using 70+ markers flow cytometry panels (PB, TT, CUSA, CSF, BM), (spatial single cell) RNA and protein profiling (TT, CUSA, BM), immunohistochemistry (TT), proteomics (CSF and PB), and 16S rRNA or shotgun metagenomic sequencing (FS). CONCLUSION The MIMIC program demonstrates the feasibility of obtaining various samples for pediatric high-grade CNS tumors. By incorporating multiple technologies in longitudinal samples, the MIMIC program provides insight into the different immune compartments and their relation to the tumor, forming the base for future clinical trials with immunotherapy.